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Here's a study from 2005 on MRI imaging of "perfusion" (delivery of arterial blood to the capillary bed) in the MS brain. The authors found that transit time for blood in MS brains was significantly prolonged compared to controls.

MTT values were found to be significantly prolonged for the enhancing and nonenhancing MS lesions and importantly for the NAWM in MS patients compared with normal control white matter.

There is a significantly prolonged time it takes for cerebral blood to get in and out of the brain in MS patients, even in normal appearing white matter...compared to controls. There is cerebral blood flow irregularity even prior to lesion formation.

This perfusion-based differentiation would not be apparent by conventional T2-weighted imaging. The magnitude of the prolonged MTT and reduced CBF indicating perfusion deficits for all these focal lesion clusters and the NAWM is provocative in itself and especially so in view of the new pathology literature and the direction it is leading us in determining factors in MS relevant to the microcirculation and ischemia. The authors interpret their findings as a primary vascular pathology rather than reflecting decreased metabolic demand.

Future studies will determine how perfusion measures will be used in demyelinating disease in the reading room. For now there is the opportunity with high-resolution perfusion MR imaging, diffusion MR imaging, and cellular and molecular imaging to look specifically at the normal and abnormal processes occurring at the endothelial level in MS. This will bring us closer to understanding the effects of intervention, including treatments targeting cellular migration and CNS surveillance, vasoreactivity, and the specific "good" and "bad" components of the inflammatory events in MS. This work by Ge et al provokes us to look at the microscopic pathology of MS by MR imaging in new ways. Whether perfusion abnormalities are cause or effect, we are delivered to a fork in the road of considerable interest.

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Good grief, I'd say so Cheer, what a great paper! The most important thing you noted: that NAWM also had this abnormality of "blood transit time" in addition to the active lesions and inactive lesions. That means it is there first.

I feel all tingly

ALso I would like to note this little chunk

and the specific "good" and "bad" components of the inflammatory events in MS

One of the problems with knocking out all immuniyt and killing all inflammation is that you get rid of the good healing componenets as well. To an extent you hanstring the possibility of healing the area.

A major challenge in multiple sclerosis research is to understand the cause or causes of remyelination failure and to devise ways of ameliorating its consequences. This requires appropriate experimental models. Although there are many models of acute demyelination, at present there are few suitable models of chronic demyelination. The taiep rat is a myelin mutant that shows progressive myelin loss and, by 1 year of age, its CNS tissue has many features of chronic areas of demyelination in multiple sclerosis: chronically demyelinated axons present in an astrocytic environment in the absence of acute inflammation. Using the taiep rat and a combination of X-irradiation and cell transplantation, it has been possible to address a number of questions concerning remyelination failure in chronic multiple sclerosis lesions, such as whether chronically demyelinated axons have undergone changes that render them refractory to remyelination and why remyelination is absent when oligodendrocyte progenitor cells (OPCs) are present. Our experiments show that (i) transplanted OPCs will not populate OPC-containing areas of chronic demyelination; (ii) myelination competent OPCs can repopulate OPC-depleted chronically demyelinated astrocytosed tissue, but this repopulation does not result in remyelination--closely resembling the situation found in some multiple sclerosis plaques; and (iii) the induction of acute inflammation in this non-remyelinating situation results in remyelination. Thus, we can conclude that axonal changes induced by chronic demyelination are unlikely to contribute to remyelination failure in multiple sclerosis. Rather, remyelination fails either because OPCs fail to repopulate areas of demyelination or because if OPCs are present they are unable to generate remyelinating oligodendrocytes owing to the presence of inhibitory factors and/or a lack of the stimuli required to activate these cells to generate remyelinating oligodendrocytes. This non-remyelinating situation can be transformed to a remyelinating one by the induction of acute inflammation.

PMID: 15699059 [PubMed - indexed for MEDLINE]

THAT is one big reason to be concerned about approaches that disallow normal body function, like killing immunity altogether so there is no inflammatory products at all availble for healing.

this makes me wonder if the reason someone like me with great inflammation control for years, since I was still normal, could be why I "suddenly" became SPMS in spite of that lack of inflammation. Damage was happening but I could not heal it? it would be possible accepting this paper.

I will be grateul to learn that Z is right, (that paper cheer, boy, not direct replication, but gosh! darned close) people will do much much better, I am guessing, than we expect.

New MRI techniques such as the analysis of magnetization transfer or diffusion have provided evidence for subtle progressive alterations in tissue integrity prior to focal leakage of the blood–brain barrier (BBB) as part of plaque formation in multiple sclerosis. Since inflammation is capable of modulating the microcirculation, we investigated the hypothesis that changes in the local perfusion might be one of the earliest signs of lesion development. 20 patients with definite relapsing–remitting multiple sclerosis were analysed with regard to cerebral blood volume, cerebral blood flow, mean transit time and apparent diffusion coefficient (ADC), as well as conventional MRI parameters, on monthly follow-up scans. Among 89 gadolinium-enhancing lesions, we selected 18 that developed during the study and met strict inclusion criteria. In these, changes of perfusion parameters were detectable not only prior to the BBB breakdown, but also prior to increases in the ADC. Our data indicate that inflammation is accompanied by altered local perfusion, which can be detected prior to permeability of the BBB.

There is a little bit of a chicken and egg thing here in that these two events-inflammation and changes in microcirculation were seen at the same time together............and both prior to BBB breakdown (BBB is endothelium by the way ADC would be stuff crossing it) but their hypothesis at the start was that inflammation would cause problems in the MICRO circulation (microcirculation meaning the teeniest and tiniest of vessels, not veins like Zamboni is talking about but they are of course attached )

Since the pathogenesis of multiple sclerosis (MS) lesions is not yet fully understood, we investigated the potential of dynamic susceptibility contrast (DSC) magnetic resonance (MR) perfusion imaging for a better characterization of lesion pathology. Twenty-five MS patients were examined on a 1.5 T scanner. A single dose of gadolinium (Gd)-DOTA contrast agent was injected, and echoplanar images were acquired every 0.5 seconds for 1 minute. From the signal intensity-versus-time curves, the relative cerebral blood volume (rCBV) was evaluated for regions in plaques and in gray and white matter. The rCBV calculated for acute, Gd-enhancing plaques was corrected for the effects of blood-brain barrier leakage, using a new correction algorithm. Acute plaques had significantly higher blood volumes than normal-appearing white matter (P < = 0.01). Chronic plaques that appeared hypointense on T(1)-weighted images had lower rCBV than T(1)-isointense plaques (P < = 0.03). Our results indicate that the acute phase in MS is accompanied by vasodilation. In later stages of gliosis, the perfusion decreases with increasing axonal injury. Although the DSC technique is less sensitive than conventional MR imaging, the information provided is essentially different from that obtained with any other MR method.

MATERIALS AND METHODS: Conventional MR imaging (which included acquisition of pre- and postcontrast transverse T1-weighted, fluid-attenuated inversion recovery, and T2-weighted images) and dynamic susceptibility contrast-enhanced T2*-weighted MR imaging were performed in 17 patients with RR-MS (five men and 12 women; median age, 38.4 years; age range, 27.6–56.9 years) and 17 control patients (seven men and 10 women; median age, 42.0 years; age range, 18.7–62.5 years). Absolute cerebral blood volume (CBV), absolute cerebral blood flow (CBF), and mean transit time (MTT) (referenced to an arterial input function by using an automated method) were determined in periventricular, intermediate, and subcortical regions of NAWM at the level of the lateral ventricles. Least-squares regression analysis (controlled for age and sex) was used to compare perfusion measures in each region between patients with RR-MS and control patients. Repeated-measures analysis of variance and the Tukey honestly significant difference test were used to perform pairwise comparison of brain regions in terms of each perfusion measure.

RESULTS: Each region of NAWM in patients with RR-MS had significantly decreased CBF (P < .005) and prolonged MTT (P < .001) compared with the corresponding region in control patients. No significant differences in CBV were found between patients with RR-MS and control patients in any of the corresponding areas of NAWM examined. In control patients, periventricular NAWM regions had significantly higher CBF (P = .03) and CBV (P = .04) than did intermediate NAWM regions. No significant regional differences in CBF, CBV, or MTT were found in patients with RR-MS.

CONCLUSION: The NAWM of patients with RR-MS shows decreased perfusion compared with that of controls

That bit about the no significant regional differences is talking about the fact that in healty controls, there was a very high cerebral blood flow in the area next tot he ventricles, the poor MSers though did not have that.

That's probably why that is where the lesions happen; that area gets a high blood flow usually.........anyone ever wonder why it was periventricular?

gee whiz.[/quote]

Last edited by mrhodes40 on Wed Mar 04, 2009 4:24 pm, edited 1 time in total.

This is exciting stuff. I mean me actually sort of understanding one of these articles . Just printed to take to my neuro. on the 11th (Ty day). OK, now you two correct me if I'm wrong here, but it looks to me like they are saying that the ishemic event is the 'origin' and maybe the lesions and inflammation are secondary? Would that then lead me to believe that we have been looking at maybe the effect and not the cause?

Great finds, Marie!!! Seems like many docs are finding the abnormal perfusion and cerebral blood flow in MS brains. The 9Tesla showed even more vascular implications. What blows me away if that the "normal appearing white matter" in the MS brains has perfusion abnormalities BEFORE lesion formation. So, like you said, Lew-the primary event appears to be hemodynamic changes in cerebral bloodflow. Just like Zamboni's supposition.

I'm happy to see that neuros are looking into these issues, because these are the docs that will be more open to the vascular approach. Save their names and university locations!
AC

Apologies if I am repeating what someone else has said or asked (I have to admit I have not gone through all the 321 posts on this board!!)

Have you all looked at the autoimmune disease Vasculitis? My neuro had put me in either the vasculitis (cerebral) or MS camp. These diseases must look or present themselves in a similar way. Also I know they treat vasculitis with cytoxan (revimmune).

but it looks to me like they are saying that the ishemic event is the 'origin' and maybe the lesions and inflammation are secondary? Would that then lead me to believe that we have been looking at maybe the effect and not the cause

I am not sure they were talking about ischemia, (did I miss it?)which would mean that oxygen is not getting to tissues and the tissues are sick specifically from that lack of oxygen, but it probably is going to be there at least a little when you are talking about such slow circulation.

the theme over all is that mean transit time MTT which means how long it takes the blood to make the whole circuit is prolonged, things are slow.

The other thing noted is that cerebral blood volume and cerebral blood flow is decreased.

ALso that these changes in the vessels and circulation precede the BBB breakdown.

Taken as a group they paint a picture of an MS brain with slow sluggish circulation. If Zambonis is right and we all have a stricture that is a "bottleneck" getting the blood to drain out through the veins, that could explain it; the slowdown at the stricture would slow down everytning else. It is hard to see how autoimmunity accounts for that.

And one paper specifically mentioned a vasodilation--widening of the vein--when the lesion is acute.

That supports the Zamboni hypothesis; that the vein in an acute lesions is backing up from reflux and that when that happens it causes the mechanical damage to the brain itself, which is then addressed by immune activation to clean it up, which then leads to the visible MS lesion/scarring.

And these studies noted that it is true of normal appearing white matter as well as areas where the existing lesions are. That suggests these circulatory changes precede the development of an MS lesion.

vasculitis

LR, Really astute!! Yes it is a disese that can look just like MS but it is caused by an autoimmune reaction that impacts the vessels themselves.

Here's the interesting thing about that: here you have a disease in which the vessels are the attacked things. Not the brain, not myelin, nope vessels. What happens? If in the brain, periventricular lesions that look just like MS. They can be clinically silent or with symptoms like MS.

But the presentation of brain vasculitis with the propensity for periventricular lesions shows that when the vessels have a problem, it shows a pattern of involvment like MS...with no "myelin reactive t cells" at all needed to create periventricular lesions. TO me it is another circumstantial affirmation that Zamboni's ideat that MS is a vein disease is on the right track

Dudes, I am the worst typist in the world, I'm lucky you put up with me. I apologise for my poor skill

Last edited by mrhodes40 on Wed Mar 04, 2009 4:58 pm, edited 1 time in total.

LR1234 wrote:Apologies if I am repeating what someone else has said or asked (I have to admit I have not gone through all the 321 posts on this board!!)

SLACKER! but seriously, welcome LR...just make sure to read the Zamboni study. That's what is most important. The rest of the posts contain even further research confirming Dr. Zamboni's observations. We're basically trying to build the case for venous insufficiency to help explain it to our neuros and docs when we request doppler scans.

Have you all looked at the autoimmune disease Vasculitis? My neuro had put me in either the vasculitis (cerebral) or MS camp. These diseases must look or present themselves in a similar way. Also I know they treat vasculitis with cytoxan (revimmune).Sorry again if I am saying something random or not relevant!!!http://vasculitis.med.jhu.edu/treatments/cytoxan.html

No apologies necessary. I researched CNS vasculitis in the beginning when my husband was first diagnosed, and I was looking into a vascular connection. Primary CNS vasculitis is rare, and the symptoms are more severe and progressive than RRMS- terrible headaches, seizures, mini strokes and dementia. A brain biopsy is the only way to confirm this disease. But the point you make is valid....MS and vasculitis are looking more and more similar, especially since both respond to revimmune and involve inflammation and periventricular lesions (good one, Marie!)
AC

no $h!t eh, dawson's got his fingers in other people's brains too?
i just read "a region of interest (ROI) was chosen from an area that encompassed the central regions of the brain the size of which was {approx} 5 mm x 5 mm x 3.1 mm thick. This ROI, chosen from a coronal slice through the midbrain, included the periventricular area that has been described as the brain region most sensitive to oxidative stress (5)."

What are the effects of Revimmune in vasculitis? Does it have to do with the really autoimmune condition called "Churg-Strauss" syndrome? At first glance it looks unrelated to MS, assuming that MS is not autoimmune.

There is some time now that several thoughts have been crossing my mind. They are mostly nonsense and stupid but I would like to share them with you.

What I was thinking is that immune suppressive treatments seem to sometimes have an effect on MS. Thinking a little clearer, I realize that there are very few drugs designed for really suppressing the immune system.

Most of the immune suppressive MS treatments are chemotherapeutic agents. Chemotherapy is a much broader class of drugs, but it has been used mainly for cancer treatments.

The aforementioned class includes antibiotic medications, additionally to anti-cancer drugs. Antibiotics are mainly designed to prevent cellular division in procaryotic organisms, which include all bacteria. Anti cancer treatments are designed for preventing human cells from dividing. Not many types of cells divide rapidly in adults. These include:

It is obvious that immune suppression and hair loss are side effects. But I am wondering. Could it be that chemotherapeutic agents owe their effectiveness in MS not to their immune suppressive properties but to their cell division inhibiting properties? Some of them are poisonous even for bacteria. Could immune suppressants and antibiotics be the two sides of the same coin? Could all this has something to do with the cause of the stenoses?

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